U.S. patent application number 13/343879 was filed with the patent office on 2012-05-10 for method for preparing rapidly disintegrating formulation for oral administration.
This patent application is currently assigned to Hanmi Pharm. Co., Ltd.. Invention is credited to Kyeong Soo Kim, Chang Hyun LEE, Jong Soo Woo, Hong Gi Yi, Ho Taek Yim.
Application Number | 20120110957 13/343879 |
Document ID | / |
Family ID | 41821804 |
Filed Date | 2012-05-10 |
United States Patent
Application |
20120110957 |
Kind Code |
A1 |
LEE; Chang Hyun ; et
al. |
May 10, 2012 |
METHOD FOR PREPARING RAPIDLY DISINTEGRATING FORMULATION FOR ORAL
ADMINISTRATION
Abstract
A method and packaging machine for preparing rapidly
disintegrating formulations for oral administration are disclosed.
The present invention is characterized in that a powdery mixture
including a pharmaceutically active ingredient and a sugar or a
sugar alcohol powder is filled into a packaging material and,
thereafter, the mixture, filled in the packaging material, is
heated. The present invention can simply and economically prepare
an oral formulation which undergoes rapid disintegration in the
oral cavity and provides for high-quality administration to
patients.
Inventors: |
LEE; Chang Hyun; (Yongin-si,
KR) ; Woo; Jong Soo; (Suwon-si, KR) ; Yi; Hong
Gi; (Suwon-si, KR) ; Kim; Kyeong Soo;
(Suwon-si, KR) ; Yim; Ho Taek; (Yongin-si,
KR) |
Assignee: |
Hanmi Pharm. Co., Ltd.
Hwaseong-si
KR
|
Family ID: |
41821804 |
Appl. No.: |
13/343879 |
Filed: |
January 5, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12654572 |
Dec 23, 2009 |
8127516 |
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13343879 |
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PCT/KR2008/003623 |
Jun 25, 2008 |
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12654572 |
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Current U.S.
Class: |
53/440 |
Current CPC
Class: |
A61P 15/18 20180101;
B65B 9/042 20130101; B30B 11/08 20130101; A61P 37/08 20180101; A61P
7/02 20180101; A61P 25/00 20180101; A61P 1/08 20180101; B65B 9/045
20130101; A61P 9/00 20180101; B30B 11/02 20130101; A61K 9/0056
20130101; A61P 11/06 20180101; A61P 25/08 20180101; A61P 29/00
20180101; A61P 25/28 20180101; A61P 31/04 20180101; A61P 25/18
20180101; A61P 15/10 20180101; A61P 7/10 20180101; A61P 13/08
20180101; A61K 9/2095 20130101; A61P 21/02 20180101; A61P 25/16
20180101; A61P 43/00 20180101; A61J 3/10 20130101; A61P 3/02
20180101; A61P 3/10 20180101; A61P 9/08 20180101; A61P 11/14
20180101; A61P 1/04 20180101; A61P 25/04 20180101 |
Class at
Publication: |
53/440 |
International
Class: |
B65B 63/08 20060101
B65B063/08 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 27, 2007 |
KR |
10-2007-0063757 |
Claims
1. A method for preparing a rapidly disintegrating formulation for
oral administration, which comprises: mixing a pharmaceutically
active ingredient with a sugar or a sugar alcohol powder to obtain
a powdery mixture, and filling the powdery mixture into a packaging
material; and heating the mixture filled in the packaging material
obtained in said mixing a pharmaceutically active ingredient to
cure the mixture.
2. The method of claim 1, wherein, said mixing a pharmaceutically
active ingredient, the powdery mixture after filled is tamped.
3. The method of claim 1, wherein the packaging material used in
said mixing a pharmaceutically active ingredient is a lower pocket
film which functions as a lower mold.
4. The method of claim 3, which, after said heating the mixture,
further comprises covering the lower pocket film with an upper
cover film.
5. The method of claim 1, wherein, in heating the mixture, the
filled mixture is heated at a temperature ranging from 200 to
1,000.quadrature. for a period of 1 to 60 seconds.
6. The method of claim 5, wherein the heating of the filled mixture
is performed by radiant heating.
7. The method of claim 1, wherein the pharmaceutically active
ingredient used in step said mixing a pharmaceutically active
ingredient is an antifebrile agent, an analgesic agent, an
anti-inflammatory agent, an anti-gastric ulcer agent, an
cardiovascular agent, a vasodilant, an antibiotic, an antitussive,
an antiasthmatic, an antiemetic, a stomach function-regulating
agent, an impotence-treating agent, a dementia-treating agent, a
benign prostatic hyperplasia-treating agent, a migrain-treating
agent, a psychostimulant, an antibacterial agent, an antihistamine,
an oral antidiabetic, an allergy-treating agent, a contraceptive, a
vitamin, an anticoagulant, a muscle-relaxing agent, a cerebral
metabolism-improving agent, an antidiuretic, an anticonvulsant, a
Parkinson disease-treating agent, an antipsychotic agent, or a
mixture thereof.
8. The method of claim 1, wherein the pharmaceutically active
ingredient used in said mixing a pharmaceutically active ingredient
is selected from the group consisting of tramadol, ibuprofen,
dexibuprofen, aspirin, acetaminophen, indomethacin, sodium
diclofenac, ketoprofen, isopropyl antipyrine, phenacetin,
flurbiprofen, phenyl butazone, etodolac, celecoxib, etoricoxib,
cimetidine, famotidine, ranitidine, nizatidine, roxatidine,
nifedipine, amlodipine, verapamil, captopril, diltiazem HCl,
propranolol, oxprenolol, nitroglycerin, enalapril, ampicillin,
amoxicillin, cephalexin, cefuroxime, cefdinir, cefadroxil,
cefprozil, cefpodoxime, cefditoren, cefaclor, cefixime, cefradine,
loracarbef, ceftibuten, cefatrizin, cefcarpen, erythromycins,
tetracyclines, quinolones, theophylline, aminopyrine, codeine
phosphate, methylephedrine HCl, dextromethorphan, noscapine,
salbutamol, ambroxol, clenbuterol, terbutaline, montelukast,
ondansetron, metoclopramide, domperidone, trimebutine maleate,
cisapride, levosulpiride, sildenafil, vadenafil, tadalafil,
udenafil, donepezil, galantamine, rivastigmine, acetyl carnitine,
memantine, zaliprodene, tamsulosin, sumatriptan, zolmitriptan,
rizatriptan, loratadine, fexofenadine, glimepiride, torsemide,
furosemide, gabapentine, pregavalin, valproate, topiramate,
carbamazepine, lamotrigine, oxcarbazepine, selegiline, risperidone,
ziprasidone, quetiapine, olanzapine, clozapine, paliperidone, a
pharmaceutically acceptable salt thereof, and a mixture
thereof.
9. The method of claim 1, wherein the pharmaceutically active
ingredient used in said mixing a pharmaceutically active ingredient
is employed in an amount ranging from 0.01 to 90% by weight based
on the total weight of the powdery mixture.
10. The method of claim 1, wherein the sugar or sugar alcohol used
in said mixing a pharmaceutically active ingredient is selected
from the group consisting of lactose, glucose, sucrose, fructose,
mannitol, sorbitol, xylitol, erythritol, ribulose, maltitol,
maltose, maltodextrin, paratinose, trehalose, dextrose, and a
mixture thereof.
11. The method of claim 1, wherein the sugar or sugar alcohol used
in said mixing a pharmaceutically active ingredient is employed in
an amount ranging from 10 to 99.99% by weight based on the total
weight of the powdery mixture.
12. The method of claim 1, wherein the powdery mixture of said
mixing a pharmaceutically active ingredient further comprises a
pharmaceutically acceptable additive selected from the group
consisting of a low temperature-melting binding agent, a
disintegrator, a lubricant, an excipient, and a mixture
thereof.
13. The method of claim 12, wherein the pharmaceutically acceptable
additive is employed in an amount ranging from 0.01 to 50 parts by
weight based on 100 parts by weight of the powdery mixture.
14. The method of claim 12, wherein the low temperature-melting
binding agent is selected from the group consisting of polyethylene
glycol, poloxamer, HCO, glycerine, propylene glycol, glycerides, a
derivative thereof, and a mixture thereof.
15. The method of claim 12, wherein the disintegrator is selected
from the group consisting of cross-linked polyvinylpyrrolidone,
cross-linked carboxymethylcellulose, sodium starch glycolate,
calcium carboxymethylcellulose, and a mixture thereof.
Description
[0001] This application is a Divisional Application of pending U.S.
application Ser. No. 12/654,572, filed Dec. 23, 2009 as an entry
into the National Phase from PCT International Application No.
PCT/KR2008/003623 filed on June 2008, which claims priority to
Korean Patent Application No. 10-2007-0063757, filed Jun. 27,
2007.
FIELD OF THE INVENTION
[0002] The present invention relates to a method and a packaging
machine for preparing an oral formulation which undergoes rapid
disintegration in the oral cavity, and the rapidly disintegrating
formulation prepared thereby.
BACKGROUND OF THE INVENTION
[0003] Rapidly disintegrating formulations are conventionally
prepared by various methods using lyophilization, a disintegrating
agent, a sublimation-like material, humidification or
dehumidification.
[0004] For example, U.S. Pat. Nos. 5,631,023 and 5,976,577 disclose
a formulation obtained by subjecting a drug-containing solution to
lyophilization. Such formulations are recently employed in
preparing products marketed by Merck, GlaxoWelcome, and
Schering-Plough under the trade names of Pepcid.TM. RPD (a
famotidine formulation), Zofran.TM. zydis (an ondansetron
formulation), and Claritin.TM. RediTabs, respectively. These
formulations disintegrate in the oral cavity within 2 to 3 seconds,
but the process for preparing them requires the use of special
equipments and packaging materials, causing reduced productivity
and high manufacturing cost.
[0005] In order to solve this problem, International Patent
Publication No. WO 99/47126 has suggested a method for preparing a
formulation which is free from a residual organic solvent, by
compressing an active ingredient together with a water-soluble
polymer binder to form a tablet and subjecting the resulting tablet
to humidification under a highly humid condition, followed by
drying. This method is known as the WOWTAB technique developed by
Yamanouchi Pharmaceuticals of Japan. In addition, International
Patent Publication No. WO 93/12769 discloses a method for preparing
a formulation by placing in a mold a suspension comprising an
active ingredient, agar and sugar, and drying the suspension at
30.degree. C. under a pressure of -760 mmHg. However, this method
suffers from low productivity and nonuniform product quality.
[0006] Alternatively, the Orasolv technique for the preparation of
a rapidly disintegrating formulation has been developed by Cima
Labs, and disclosed in U.S. Pat. Nos. 5,178,878 and 6,024,981. The
marketed product obtained by the Orasolv technique is represented
by Zimig.TM. Rapimelt (a zolmitriptan formulation) marketed by
Astrazeneka, but it does not undergo satisfactory oral
disintegration and it gives an uncomfortable feeling when
administered because of the generation of effervescent gases.
[0007] U.S. Pat. No. 3,885,026 teaches a method for preparing a
porous tablet by mixing a volatile excipient such as urethane,
urea, ammonium carbonate and naphthalene with other tablet
components, compressing the mixture to form a tablet, and heating
the tablet to remove the volatile excipient.
[0008] Further, U.S. Pat. No. 4,134,943 describes a method for
preparing a porous tablet by mixing a solvent having a melting
point ranging from -30 to 25.degree. C. (e.g., water, cyclohexane,
benzene, tert-butanol) with tablet components, cooling the mixture
to solidify said solvent, compressing the solid mixture to form a
tablet, and removing the solvent therefrom through evaporation.
However, such porous tablets may be toxic due to the residual
excipient or organic solvent.
[0009] As mentioned above, conventional rapidly disintegrating
formulations are prepared by forming a tablet comprising a specific
material removable by sublimation, evaporation or dehumidification,
and then removing the corresponding specific material therefrom, so
that they become porous and allow rapid penetration of saliva.
However, such conventional formulations having deliberately formed
pores suffer from significant deterioration of physical properties
or undesired dimensional changes.
[0010] Therefore, there is need for developing rapidly
disintegrating formulations capable of being easily manufactured
and providing comfortable feeling to a patient during the
administration without causing problems resulting from above
mentioned conventional methods.
SUMMARY OF THE INVENTION
[0011] Accordingly, it is an object of the present invention to
provide a simple method and a packaging machine for preparing an
oral formulation which undergoes rapid disintegration in the oral
cavity and provides enhanced patient comfort during
administration.
[0012] In accordance with one aspect of the present invention,
there is provided a method for preparing a rapidly disintegrating
formulation for oral administration, comprising: (A) mixing a
pharmaceutically active ingredient with a sugar or a sugar alcohol
powder to obtain a powdery mixture, and filling the powdery mixture
into a packaging material; and (B) heating the mixture filled in
the packaging material obtained in step (A) to cure the
mixture.
[0013] In accordance with another aspect of the present invention,
there is provided the rapidly disintegrating formulation for oral
administration prepared by said method.
[0014] In accordance with still another aspect of the present
invention, there is provided a packaging machine for preparing a
rapidly disintegrating formulation for oral administration,
comprising: a film feeding unit to feed a forming film; a film
shaping unit to shape the forming film, thus forming a lower pocket
film provided with a pocket having a container shape; a drug
material feeding unit to fill or input a powdery mixture or a
tablet, formed by pressing the powdery mixture to have a
predetermined shape, into the pocket of the lower pocket film; a
heating unit to heat the filled mixture or tablet, thus melting and
unifying the filled mixture or tablet; and a sealing unit to attach
an upper cover film to the lower pocket film.
[0015] In accordance with the present invention, an oral
formulation which undergoes rapid disintegration in the oral cavity
and allows for enhanced patient comfort during administration can
be prepared through a single process line in a simple and
economical manner, without deterioration of desired physical
properties or undergoing undesirable dimensional changes that occur
when a conventional method involving a deliberate pore-forming step
is used.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] The above and other objects, features and advantages of the
present invention will be more clearly understood from the
following detailed description taken in conjunction with the
accompanying drawings, in which:
[0017] FIG. 1 is a block diagram showing the construction of a
packaging machine for preparing a rapidly disintegrating
formulation for oral administration, according to an embodiment of
the present invention;
[0018] FIG. 2 is a cross sectional view of a drug material feeding
unit of the packaging machine for preparing the rapidly
disintegrating formulation for oral administration according to the
present invention;
[0019] FIG. 3 is a perspective view showing a critical part of the
drug material feeding unit of the packaging machine for preparing
the rapidly disintegrating formulation for oral administration
according to the present invention;
[0020] FIG. 4 is a cross sectional view of a heating unit of the
packaging machine for preparing the rapidly disintegrating
formulation for oral administration according to the present
invention;
[0021] FIG. 5 is a block diagram showing the construction of a
packaging machine for preparing a rapidly disintegrating
formulation for oral administration, according to another
embodiment of the present invention;
[0022] FIG. 6 is a cross sectional view of a pressing unit of the
packaging machine for preparing the rapidly disintegrating
formulation for oral administration according to the embodiment of
FIG. 5;
[0023] FIG. 7 is a block diagram showing the construction of a
packaging machine for preparing a rapidly disintegrating
formulation for oral administration, according to still another
embodiment of the present invention; and
[0024] FIG. 8 is a cross sectional view of a suction unit of the
packaging machine for preparing the rapidly disintegrating
formulation for oral administration according to the embodiment of
FIG. 7.
DETAILED DESCRIPTION OF THE EMBODIMENT
[0025] Hereinafter, the present invention will be described in
detail.
[0026] The inventive method is characterized by melt-combining a
mixture of a pharmaceutically active ingredient and a sugar or a
sugar alcohol having numerous inherent pores through filling the
mixture in a packaging material (step (A)) and heating (step (B))
to form a rapidly disintegrating formulation possessing inherent
pores, unlike the conventional method which deliberately creates
pores through sublimation, evaporation or dehumidification.
[0027] The inventive method does not result in deteriorated
physical properties of the formulation or undesired dimensional
changes, and it is very simple and inexpensive.
[0028] <Step (A)>
[0029] A composition (mixed powder) used in the preparation of the
inventive formulation comprises a pharmaceutically active
ingredient and a sugar or a sugar alcohol, and the composition may
further comprise a pharmaceutically acceptable additive.
[0030] Hereinafter, the components of the inventive composition for
a rapidly disintegrating formulation are described in detail as
follows:
[0031] (1) Pharmaceutically Active Ingredient
[0032] {circle around (1)} Antifebrile, analgesic or
anti-inflammatory agents, e.g., tramadol, ibuprofen, dexibuprofen,
aspirin, acetaminophen, indomethacin, sodium diclofenac,
ketoprofen, isopropyl antipyrine, phenacetin, flurbiprofen, phenyl
butazone, etodolac, celecoxib, etoricoxib and pharmaceutically
acceptable salts thereof.
[0033] {circle around (2)} Anti-gastric ulcer agents, e.g.,
cimetidine, famotidine, ranitidine, nizatidine, roxatidine and
pharmaceutically acceptable salts thereof.
[0034] {circle around (3)} Cardiovascular agents or vasodilants,
e.g., nifedipine, amlodipine, verapamil, captopril, diltiazem HCl,
propranolol, oxprenolol, nitroglycerin, enalapril and
pharmaceutically acceptable salts thereof.
[0035] {circle around (4)} Antibiotics, e.g., ampicillin,
amoxicillin, cephalexin, cefuroxime, cefdinir, cefadroxil,
cefprozil, cefpodoxime, cefditoren, cefaclor, cefixime, cefradine,
loracarbef, ceftibuten, cefatrizin, cefcarpen, erythromycins,
tetracyclines, quinolones and pharmaceutically acceptable salts
thereof.
[0036] {circle around (5)} Antitussives or antiasthmatics, e.g.,
theophylline, aminopyrine, codeine phosphate, methylephedrine HCl,
dextromethorphan, noscapine, salbutamol, ambroxol, clenbuterol,
terbutaline, montelukast and pharmaceutically acceptable salts
thereof.
[0037] {circle around (6)} Antiemetics or stomach
function-regulating agents, e.g., ondansetron, metoclopramide,
domperidone, trimebutine maleate, cisapride, levosulpiride and
pharmaceutically acceptable salts thereof.
[0038] {circle around (7)} Impotence-treating agents, e.g., agents
that block the cleavage of nitrogen monoxide, including sildenafil,
vadenafil, tadalafil, udenafil and pharmaceutically acceptable
salts thereof.
[0039] {circle around (8)} Dementia-treating agents, e.g.,
donepezil, galantamine, rivastigmine, acetyl carnitine, memantine,
zaliprodene and pharmaceutically acceptable salts thereof.
[0040] In addition to the above, other active ingredients may
include a benign prostatic hyperplasia-treating agent such as
tamsulosin; a migrain-treating agent such as sumatriptan,
zolmitriptan and rizatriptan; a psychostimulant; an antibacterial
agent; an antihistamine such as loratadine and fexofenadine; an
oral antidiabetic such as glimepiride; an allergy-treating agent; a
contraceptive; a vitamin; an anticoagulant; a muscle-relaxing
agent; a cerebral metabolism-improving agent; an antidiuretic such
as torsemide and furosemide; an anticonvulsant such as gabapentine,
pregavalin, valproate, topiramate, carbamazepine, lamotrigine and
oxcarbazepine; a Parkinson disease-treating agent such as
selegiline; an antipsychotic agent such as risperidone,
ziprasidone, quetiapine, olanzapine, clozapine and paliperidone;
and pharmaceutically acceptable salts thereof; and a biological
vaccine.
[0041] The active ingredient may be employed in an amount ranging
from 0.01 to 90% by weight, preferably 0.02 to 70% by weight, based
on the total weight of the powdery mixture.
[0042] (2) Sugar or Sugar Alcohol
[0043] The sugar or sugar alcohol plays the role of maintaining the
shape of the formulation, determines its dissolution rate, and
provides sweet taste, solubility, and comfortable touch in the oral
cavity. Therefore, it is preferred that the sugar or sugar alcohol
is sweet and water soluble. Representative examples thereof include
lactose, glucose, sucrose, fructose, mannitol, sorbitol, xylitol,
erythritol, ribulose, maltitol, maltose, maltodextrin, paratinose,
trehalose, dextrose and a mixture thereof.
[0044] The sugar or sugar alcohol may be employed in an amount
ranging from 10 to 99.99% by weight, preferably 20 to 95% by
weight, based on the total weight of the powdery mixture. When the
amount is less than 10% by weight, the sweet and comfortable taste
in the oral cavity is not good.
[0045] (3) Pharmaceutically Acceptable Additive
[0046] In order to enhance both the fluidity of the powdery mixture
before filling and the physical properties of the formulation, and
also to provide comfortable feeling to a patient during the
administration, one more pharmaceutically acceptable additives in
addition to the pharmaceutical active ingredient and the sugar or
sugar alcohol may be added to the inventive formulation. Examples
thereof are a low temperature-melting binding agent, a
disintegrator, a lubricant and an excipient (e.g., sweetening
agent, filling agent).
[0047] The low temperature-melting binding agent functions to
maintain the hardness and the shape of the rapidly disintegrating
formulation during its handling and storage. The low
temperature-melting binding agent may be any one of conventional
binding agents and have a melting point of 100.degree. C. or below,
of which examples include polyethylene glycol, poloxamer, HCO,
glycerine, propylene glycol, glyceride, a derivative thereof, and a
mixture thereof. Preferred among them are polyethylene glycol 200,
300, 400, 600, 1000, 1500, 2000, 3000, 4000, 6000, 8000 and 20000,
poloxamer 188, 237, 338 and 407, HCO-50, HCO-60, glycerine,
glyceryl behenate, glyceryl monostearate, glyceryl monooleate,
propylene glycol, medium-chain triglyceride and fatty acid
glyceride.
[0048] The disintegrator which is used for the more rapid
disintegration of the formulation in the oral cavity may be
selected from the group consisting of cross-linked
polyvinylpyrrolidone, cross-linked carboxymethylcellulose, sodium
starch glycolate, calcium carboxymethylcellulose, and a mixture
thereof.
[0049] The lubricant may be selected from the group consisting of
magnesium stearate, talc, silica, sodium stearyl fumarate, valine,
sucrose fatty acid ester, hydrogenated castor oil, and a mixture
thereof.
[0050] As the excipient, a sweetening agent such as aspartame,
stevioside, sucralose and acesulfame, or a filling agent such as
microcrystalline cellulose, calcium phosphate, calcium carbonate
and starch may be used.
[0051] Each additive may be used in an amount of 0.01 to 50 parts
by weight, preferably 0.1 to 30 parts by weight, based on 100 parts
by weight of the mixture.
[0052] In the present invention, the pharmaceutically active
ingredient, the sugar or sugar alcohol powder, and the optional
pharmaceutically acceptable additive may be mixed in accordance
with the conventional dry or wet mixing method. All components are
uniformly blended in a mixer by the dry mixing method. The wet
mixing method comprises subjecting a portion or all of the
components to wet granulation and drying the resulting wet
granules.
[0053] Subsequently, a packaging material, e.g., a lower pocket
film which functions as a lower mold for packaging, is filled with
a predetermined amount of the mixed powder thus obtained. Suitable
for the packaging material may be aluminum, polyvinyl chloride
(PVC) or polyvinylidene chloride (PVDC). In particularly, preferred
is aluminum which can stand heat ranging from 200 to 1,000.degree.
C. In case of employing PVC or PVDC, the filled powder alone may be
selectively heated, thereby preventing heat deformation of the
packaging material. The lower pocket film for packaging having a
particular character or design may be used to obtain the
formulation having such character or design as an identification
mark. Preferably, after filling, the mixed powder in the packaging
material may be tamped using a tamping bar to enhance its
uniformity.
[0054] <Step (B)>
[0055] The mixture filled in the packaging material obtained in the
present invention is heated at a temperature ranging from 200 to
1,000.degree. C. for a period of 1 to 60 seconds, preferably 1 to
30 seconds, using radiant heat to cure the filled mixture and
obtain a desired rapidly disintegrating formulation. The adherence
of the formulation to the packaging material surface may be
prevented by adjusting the component ratio of the mixed powder and
the heating condition.
[0056] In the present invention, the mixture is exposed to a high
temperature for a very short period, minimizing heat decomposition
of the active ingredient. The exposure time may depend on the
nature of each of the used components. A heating apparatus such as
a halogen lamp, an infrared-ray(IR) radiator and a heating tunnel
may be used, the halogen lamp being preferred.
[0057] Then, an upper cover film may be placed to cover the lower
pocket film and form a certain shape of the formulation, to
complete the encasing of the formulation. The upper cover film may
be made of aluminum, but not limited thereto, and it may be any one
of conventional materials which is allowable for an easy
peeling.
[0058] The cured mixture obtained in step (B) may be formulated in
the form of a tablet, a pill, a capsule or a dispersant, preferably
a tablet, in accordance with the conventional method.
[0059] As described above, in accordance with the inventive method,
an oral formulation which undergoes rapid disintegration in the
oral cavity and provides enhanced patient comfort during
administration can be prepared in a simple and economical manner,
without deterioration of physical properties or undesirable
dimensional changes that occur when a conventional method involving
a deliberate pore-forming step is used.
[0060] The following Examples are intended to further illustrate
the present invention without limiting its scope.
Example 1
[0061] 20 mg of famotidine as an active ingredient and 300 mg of
xylitol as a sugar alcohol were uniformly mixed, and the mixed
powder was filled into a pocket-shaped aluminum film (a lower
pocket film). Then, the mixture filled in the pocket film was
heated using an infrared-ray lamp at about 800.degree. C. for 6 sec
to perform its curing. Then, an aluminum film cover (an upper cover
film) was placed on the lower pocket film and sealed, to obtain an
inventive rapidly disintegrating formulation tablet.
Example 2
[0062] The procedure of Example 1 was repeated except that the
filled mixture was heated using an infrared-ray lamp at about
400.degree. C. for 20 sec, to obtain an inventive rapidly
disintegrating formulation tablet.
Example 3
[0063] The procedure of Example 1 was repeated except that the
filled mixture was heated using an infrared-ray lamp at about
600.degree. C. for 15 sec, to obtain an inventive rapidly
disintegrating formulation tablet.
Example 4
[0064] The procedure of Example 1 was repeated except that the
filled mixture was heated using an infrared-ray lamp at about
400.degree. C. for 30 sec, to obtain an inventive rapidly
disintegrating formulation tablet.
Example 5
[0065] The procedure of Example 1 was repeated except that the
filled mixture was heated using an infrared-ray lamp at about
1000.degree. C. for 2 sec, to obtain an inventive rapidly
disintegrating formulation tablet.
Examples 6 to 10
[0066] The procedure of Example 1 was repeated using each of 300 mg
of sorbitol, a mixture of 150 mg of xylitol and 150 mg of sorbitol,
300 mg of maltitol, 300 mg of mannitol and 300 mg of erythritol as
the sugar alcohol component, not 300 mg of xylitol, to obtain
respective rapidly disintegrating formulation tablets.
Examples 11 to 20
[0067] The procedure of Example 1 was repeated using 300 mg of each
of lactose, glucose, sucrose, fructose, maltose, paratinose,
ribulose, maltodextrin, trehalose and dextrose as a sugar
component, without using xylitol as the sugar alcohol component, to
obtain respective rapidly disintegrating formulation tablets.
Examples 21 to 45
[0068] The procedure of Example 1 was repeated using each of mg of
tramadol HCl, 50 mg of ibuprofen, 30 mg of dexibuprofen, 50 mg of
aspirin, 50 mg of celecoxib, 20 mg of vadenafil HCl, 5 mg of
amlodipine, 50 mg of cefdinir, 50 mg of teofilin, 4 mg of
ondansetron, 50 mg of sildenafil, 5 mg of donepezil, 4 mg of
galantamine, 0.2 mg of tamsulosin HCl, mg of sumatriptan, 4 mg of
montelukast, 10 mg of loratadine, 2 mg of glimepiride, 30 mg of
fexofenadine, 5 mg of torsemide, 50 mg of topiramate, 2 mg of
risperidone, 10 mg of olanzapine, 2.5 mg of zolmitriptan and 5 mg
of montelukast as an active ingredient, not 200 mg of famotidine,
to obtain respective rapidly disintegrating formulation
tablets.
Examples 46 to 51
[0069] The procedure of Example 1 was repeated except that each of
10 mg of PEG 6000, 20 mg of PEG 6000, 40 mg of PEG 6000, 10 mg of
poloxamer 188, 20 mg of poloxamer 188 and 40 mg of poloxamer 188 as
a lower temperature-melting binding agent was further added to the
mixed powder, to obtain respective rapidly disintegrating
formulation tablets.
Example 52
[0070] The procedure of Example 1 was repeated except that 300 mg
of mannitol was dissolved in a mixture of 10 mg of water and 10 mg
of ethanol, the solution was subjected to wet granulation, and the
resulting wet granules were dried and used as the sugar alcohol,
not 300 mg of xylitol, to obtain an inventive rapidly
disintegrating formulation tablet.
Example 53
[0071] The procedure of Example 1 was repeated except that 150 mg
of xylitol and 150 mg of mannitol were dissolved in a mixture of 5
mg of water and 10 mg of ethanol, the solution was subjected to wet
granulation, and the resulting wet granules were dried and used as
the sugar alcohol, not 300 mg of xylitol, to obtain an inventive
rapidly disintegrating formulation tablet.
Example 54
[0072] The procedure of Example 1 was repeated except that 50 mg of
xylitol and 250 mg of mannitol were dissolved in a mixture of 5 mg
of water, 10 mg of ethanol and 5 mg of medium-chain triglyceride
(MTC oil), the solution was subjected to wet granulation, and the
resulting wet granules were dried and used as the sugar alcohol,
not 300 mg of xylitol, to obtain an inventive rapidly
disintegrating formulation tablet.
Example 55
[0073] The procedure of Example 1 was repeated except that 50 mg of
xylitol and 250 mg of mannitol were dissolved in a mixture of 5 mg
of water, 10 mg of ethanol and 5 mg of medium-chain triglyceride
(MTC oil), the solution was subjected to wet granulation, and the
resulting wet granules were dried and used as the sugar alcohol,
not 300 mg of xylitol, and that 30 mg of cross-linked
polyvinylpyrrolidone as a disintegrator was further added to the
mixed powder to obtain an inventive rapidly disintegrating
formulation tablet.
Comparative Example 1
[0074] Gaster.TM. oral disintegrating tablet (containing 20 mg of
famotidine) commercially available from Dong-A Pharmaceutical Co.,
Ltd. was used as a comparative formulation. The Gaster.TM. oral
disintegrating tablet was prepared by a conventional WOWTAB
technique.
Test Example 1
Disintegration Test
[0075] [Disintegration Rate]
[0076] The disintegration rate (sec) of the tablet was determined
in accordance with the General Test disclosed in Korean
Pharmaceutica by dropping it to 5 ml of distilled water (in a
spoon) maintained at room temperature and then measuring the time
for it to become completely disintegrated.
[0077] [Disintegration Rate in a Test Tube]
[0078] A 90 mm-diameter filter paper was placed in a 100.times.10
mm Petri dish. 7 ml of distilled water was poured into the Petri
dish and the Petri dish was allowed to be tilt, to complete overall
wetting of the filter paper. The disintegration rate (sec) of the
tablet in a test tube was determined by placing it on the wet
filter paper and then measuring the time for it to get completely
wet by a capillary phenomenon.
[0079] [Disintegration Rate in an Oral Cavity]
[0080] The disintegration rate (sec) of the tablet in an oral
cavity was determined by placing it on a healthy male adult's dry
tong and then measuring the time for it to become completely
disintegrated and dissolved while rubbing.
[0081] The disintegration rates and the overall tastes of the
tablets obtained in Examples 1 to 55 and Comparative Example were
determined, as described above. The results are shown in Table
1.
TABLE-US-00001 TABLE 1 Disintegration Disintegration Disintegration
rate in a test rate in an oral rate (sec) tube (sec) cavity Taste
Ex. 1 1 2 2 Very smooth Ex. 6 2 3 3 Very smooth Ex. 7 2 2 3 Very
smooth Ex. 8 4 15 20 smooth Ex. 9 3 8 15 smooth Ex. 10 3 7 10 Very
smooth Ex. 11 5 14 18 smooth Ex. 12 4 8 12 smooth Ex. 13 4 9 12
smooth Ex. 14 4 10 14 smooth Ex. 15 3 8 12 smooth Ex. 16 5 11 22
smooth Ex. 17 4 15 30 smooth Ex. 18 6 20 33 smooth Ex. 19 3 7 10
smooth Ex. 20 3 8 14 smooth Ex. 46 1 2 3 Very smooth Ex. 47 1 2 3
Very smooth Ex. 48 2 5 7 Very smooth Ex. 49 2 3 4 Very smooth Ex.
50 3 4 6 Very smooth Ex. 51 3 5 8 Very smooth Ex. 52 1 2 2 Very
smooth Ex. 53 2 3 3 Very smooth Ex. 54 2 2 3 Very smooth Ex. 55 1 2
3 Very smooth Comp. 10 56 45 smooth Ex. 1
[0082] As can be seen in Table 1, the inventive tablets obtained in
Examples underwent complete disintegration in the oral cavity
within 2 to 33 seconds, and the resultant suspensions had
satisfactory tastes appropriate for oral administration. In
contrast, the Gaster.TM. oral disintegrating tablet of Comparative
Example 1 required more than 40 seconds for complete disintegration
in the oral cavity.
[0083] Hereinafter, a packaging machine for preparing rapidly
disintegrating formulations in a mass production manner using the
preparing method of the present invention will be described in
detail.
[0084] Blister packaging machines are typical pharmaceutical
packaging machines. The term blister packaging means a packaging
method in which a container-shaped part is formed in a planar film
made of synthetic or metal, the container-shaped part is filled
with an object, the container-shaped part is covered with a cover
which is sealed by adhesion, and it is drawn to a predetermined
size and cut, thus forming a unit of a packaging body. In the
beginning, in pharmaceutical companies, such blister packaging
methods were developed and used to pack a tablet or a capsule in
one pack. At present, the blister packaging methods are widely used
in confectionery production or in processes of producing cosmetics
or household articles. Unlike other packaging methods, in the
blister packaging method, because a transparent film is used,
products are easily observable, and, because the products are
packaged using a film, the shape in which the products are packaged
by the film, can be easily modified by modifying the forming mold
which, for example, has a shape corresponding to the products or
other various shapes. Furthermore, due to the use of a hard film,
products can be reliably protected. In addition, when it is desired
to use the products, because it is easy to open the products,
anybody can use the products. As well, there is an advantage in
that the portability is superior.
[0085] Such a typical pharmaceutical packaging machine has the
following components:
[0086] (1) a film feeding unit, for feeding a planar forming film
used for manufacturing a lower pocket film for the packaging. The
film feeding unit includes an uncoiler, from which a forming film
is unwound and is fed, and a draw-off means, which draws a forming
film from the uncoiler at a constant speed.
[0087] (2) a film shaping unit, including a mold having a shape
corresponding to the desired shaped of a product, which works by
placing the forming film on the mold, and pressing the forming film
by moving a pressing rod downwards, thus forming a depressed pocket
in the forming film. The film shaping unit may include a
pre-heating part, which pre-heats the forming film to enhance the
plasticity of the film.
[0088] (3) a content input unit, having a hopper containing
contents therein, and inputting contents into the pocket of the
film.
[0089] (4) a sealing unit, for attaching an upper cover film to
seal the lower pocket film, into which the contents are put. The
sealing unit includes an uncoiler, around which a cover film is
wound in the shape of a roll, and a sealing device.
[0090] (5) a cutting unit, for cutting products into a packaging
unit. As necessary, the cutting unit may include an embossing
device for expressing a product number or date of manufacture, a
slitting device for forming a perforated line, and a punching
device for conducting a punching operation.
[0091] (6) a control unit, installed in the front surface of the
machine. The control unit controls the operation of the machine
according to the manipulation of a worker. For example, the control
unit may be realized by a control panel.
[0092] The operation of the pharmaceutical packaging machine having
the above-mentioned construction will be described below. The
forming film, which has been wound around the uncoiler of the film
feeding unit, is fed at a constant speed and is pre-heated by the
pre-heating unit of the film shaping unit at a temperature suitable
for forming. The forming film is thereafter immediately pressed by
the pressing rod, such that pockets for containing contents therein
are formed in the forming film, each of the pockets having a shape
of the container. As such, the forming film having the pockets
becomes the lower pocket film for the packaging. Subsequently,
contents (e.g., pills) are inserted into the respective pockets by
the content input unit. The lower pocket film, containing the
contents therein, is supplied to the sealing unit and is integrated
with the upper cover film by pressing, thus sealing the contents.
Thereafter, it is cut by the cutting unit into a packaging
unit.
[0093] In principle, a pharmaceutical packaging machine according
to the present invention has the above-mentioned construction and
operation, but the detailed shape and function thereof are not
limited. In other words, any packaging machine can be used in the
present invention, so long as it has a basic blister packaging
function.
[0094] FIG. 1 is a block diagram showing the construction of a
packaging machine for preparing a rapidly disintegrating
formulation for oral administration, according to an embodiment of
the present invention. FIG. 2 is a cross sectional view of a drug
material feeding unit 130 of the packaging machine.
[0095] The packaging machine 100 for preparing the rapidly
disintegrating formulation for oral administration according to the
present invention has as basic components a film feeding unit 110,
a film shaping unit 120, a sealing unit 170, a cutting unit 180 and
a control unit 190, similar with the typical pharmaceutical
packaging machine. However, the packaging machine 100 further
includes the drug material feeding unit 130, which inputs a powdery
mixture 20 or a tablet 22, which is formed by pressing the powdery
mixture 20 to form a predetermined shape, into a pocket 10a of a
lower pocket film 10, unlike the typical pharmaceutical packaging
machine having the content input unit. As well, the packaging
machine 100 further includes a heating unit 160, which heats the
mixture or tablet, input into the lower pocket film 10, so as to
melt and unify the mixture or tablet.
[0096] Therefore, the arrangement sequentially by position is the
film feeding unit 110, the film shaping unit 120, the drug material
feeding unit 130, the heating unit 160, the sealing unit 170 and
the cutting unit 180.
[0097] The drug material feeding unit 130 inputs the powdery
mixture 20, which is obtained by mixing a pharmaceutically active
ingredient with a sugar or a sugar alcohol powder, or inputs the
tablet 22, formed by pressing the powdery mixture 20, into a pocket
10a formed in the lower pocket film 10.
[0098] For example, in the drug material feeding unit 130, an
appropriate amount of powdery mixture 20 is put into a hole at a
powder pressing position and pressed, thus forming a tablet 22 into
a predetermined shape. Thereafter, the tablet 22 is input into a
pocket 10a of the lower pocket film 10, which has been previously
disposed at a position corresponding to a drug material discharge
position.
[0099] In this embodiment, the drug material feeding unit 130
includes a filling disk 132, which has at least two filling holes
132a which alternate between the powder pressing position and the
drug material discharge position. The powdery mixture 20 is piled
onto the upper surface of the filling disk 132. The drug material
feeding unit 130 further includes a lower disk 134, which is
provided under the filling disk 132 and has an opening 134a, which
opens the filling hole 132a, disposed at the drug material
discharge position, while the filling hole 132a, disposed at the
powder pressing position, is closed by the lower disk 134. The drug
material feeding unit 130 further includes pressing rods 136, which
are provided above respective filling holes 132a so that the
pressing rods 136 move downwards into the corresponding filling
holes 132a at the same time to press a powdery mixture 20 or
discharge a tablet 22 and then move upwards, and a hopper 138,
which feeds the powdery mixture 20 onto the filling disk 132.
[0100] Here, the filling disk 132 is a circular plate. At least two
filling holes 132a are formed through the filling disk 132 at
positions spaced apart from each other at regular angular
intervals. The filling holes 132a are moved by rotation of the
filling disk 132 and are thus alternately positioned above the
powder pressing position and the drug material discharge
position.
[0101] Therefore, after the powdery mixture 20 is fed from the
hopper 138 onto the filling disk 132, when the filling disk 132 is
rotated and the filling holes 132a are thus respectively moved
towards the powder pressing position and the drug material
discharge position, some of the piled powdery mixture 20 is
naturally drawn into the corresponding filling hole 132a. The
filling disk 132 is stopped when this filling hole 132a reaches the
powder pressing position. Subsequently, the corresponding pressing
rod 136 is moved into this filling hole 132a to press the powdery
mixture 20 in the filling hole 132a, thus forming a tablet 22
having a satisfactory unifying force. Thereafter, the pressing rod
136 is moved upwards, and the filling disk 132 is rotated at a
predetermined angle such that this filling hole 132a is disposed at
the drug material discharge position. Subsequently, the
corresponding pressing rod 136 is moved downwards into this filling
hole 132a, thus discharging the tablet 22 downwards to the outside
of the filling hole 132a. The discharged tablet 22 falls downwards
into a pocket 10a of the lower pocket film 10 which is previously
disposed at the drug material discharge position.
[0102] Of course, because the all pressing rods 136 are moved
upwards or downwards at the same time, the powder pressing
operation and the tablet discharge operation are conducted at the
same time.
[0103] In brief, the operation of the drug material feeding unit
130 comprises a step of filling a powdery mixture 20 into a
corresponding filling hole, a step of pressing the filled powdery
mixture 20, and a step of discharging the tablet 22.
[0104] Here, each of the filling step and the pressing step may be
performed two or more times to set the amount of contents of the
tablet 22 to an appropriate degree. For this, the number of filling
holes 132a and the number of pressing rods 136 may be increased by
as many as necessary. In this case, the rotating steps of the
filling disk 132 are further subdivided.
[0105] Of course, in further consideration of the number of the
filling and pressing steps, if a required amount of active
ingredient of an objective product, that is, a rapidly
disintegrating formulation, is relatively small, or if the density
of active ingredient is relatively high, the number of steps may be
reduced.
[0106] Meanwhile, when forming a tablet 22 at the powder pressing
position, when moving the formed tablet 22 from the powder pressing
position to the drug material discharge position, or when the
tablet 22 is disposed at the drug material discharge position, some
powdery mixture 20, which has been around the filling hole 132a
having the tablet 22 therein, must be prevented from undesirably
entering the filling hole 132a, to enhance the marketability of the
tablet 22 and the sealing ability between the upper cover film and
the lower pocket film 10. To achieve the above purpose, as shown in
FIG. 3, a powder blocking means 137, which extends from a position
ahead of the powder pressing position to a position behind the drug
material discharge position, may be provided on the upper surface
of the filling disk 132. The powder blocking means 137 may have a
plate shape.
[0107] In the drawings, reference numeral 112 denotes a guide
block, which guides movement of the lower pocket film 10, and
reference numeral 139 denotes a leakage prevention plate, which
prevents the powdery mixture 20 on the filling disk 132 from being
undesirably separated from the filling disk 132.
[0108] Although the machine of the present invention has been
illustrated as being constructed such that powdery mixture 20 is
formed into a tablet 22 and then is input into the lower pocket
film 10, it may be constructed such that the powdery mixture 20 is
directly input into the lower pocket film 10.
[0109] Meanwhile, the heating unit 160 heats the mixture or tablet,
input into the lower pocket film 10, at a temperature ranging from
200.degree. C. to 1,000.degree. C. for a relatively short period of
from several seconds to several tens seconds, thus melting and
unifying the mixture or tablet while minimizing decomposition of a
pharmaceutically active ingredient. In the case of the powdery
mixture, the powdery mixture is melted and unified, thus forming a
unified tablet shape. In the case of the tablet, the unifying force
thereof can be further increased.
[0110] FIG. 4 is a schematic view showing the construction of a
representative example of the heating unit 160.
[0111] The heating unit 160 includes a heat generator 162, which is
provided above the lower pocket film 10 that is provided on the
guide block 112 so as to be movable. The heat generator 162 heats a
mixture or tablet, which is filled into the lower pocket film 10,
thus melting and unifying the mixture or tablet. The heating unit
160 further includes a shutter 164, which is retractably inserted
into a space between the heat generator 162 and the lower pocket
film 10 to allow or interrupt the heat transfer from the heat
generator 162 to the mixture or tablet, thus controlling the time
over which the mixture or tablet is exposed to heat, and making it
possible to repeatedly conduct the heating operation.
[0112] Here, a halogen lamp, an infrared lamp or the like, which
can heat an object to a temperature of 200.degree. C. or more, may
be used as the heat generator 162. As necessary, several lamps may
be used as the heat generator 162.
[0113] Furthermore, a plate, which can cover the lower pocket film
10 and intercept heat transferred from the heat generator 162 to
the lower pocket film 10, may be used as the shutter 164. The time
for which the lower pocket film 10 is exposed to heat by the
retraction of the shutter 164, may be varied according to the kind
of ingredients in the drug material and the material used for the
lower pocket film 10.
[0114] While the lower pocket film 10 is advanced, the opening and
closing of the shutter 164 are repeated, so that mixtures or
tablets, which are in the lower pocket film 10, are heated for a
predetermined exposure time. This operation is repeatedly and
continuously conducted.
[0115] Meanwhile, as shown in FIG. 5, the packaging machine 100 for
preparing a rapidly disintegrating formulation for oral
administration according to the present invention may further
include a pressing unit 140, which is provided between the drug
material feeding unit 130 and the heating unit 160. The pressing
unit 140 serves to press a mixture or tablet, which is input into
the corresponding pocket 10a of the lower pocket film 10 by the
drug material feeding unit 130, thus forming a tablet 22 having a
shape corresponding to that of the pocket 10a.
[0116] As shown in FIG. 6, the pressing unit 140 includes tamping
rods 142, which are moved downwards into the corresponding pockets
10a of the lower pocket film 10 to press mixtures or tablets and
then are moved upwards.
[0117] Here, to press the mixtures or tablets in multiple steps and
thus form the mixtures or tablets into a shape more similar to that
of the corresponding pocket 10a, several tamping rods 142 having
different shapes may be provided at front and rear positions to
press the mixtures or tablets. In the drawing, the tamping rods 142
are illustrated as comprising first tamping rods, which primarily
press the perimeters of the mixtures or tablets, and second tamping
rods, which secondarily press the central portions of the mixtures
or tablets.
[0118] Furthermore, each tamping rod 142 can be rotated at a fine
angle in a state of pressing the corresponding mixture or tablet
filled in the pocket film. Therefore, the mixture or tablet can be
shaped to have an even shape in the pocket 10a without becoming
malformed and leaning to one side.
[0119] Meanwhile, as shown in FIG. 7, the packaging machine 100 for
preparing a rapidly disintegrating formulation for oral
administration according to the present invention may further
include a suction unit 150, which is provided between the drug
material feeding unit 130 and the heating unit 160. The suction
unit 150 generates suction pressure on the lower pocket film 10, in
which mixtures or tablets are input, thus suctioning and removing
undesirable fine powder from the lower pocket film 10, thereby
enhancing the marketability of the products and sealing ability of
the upper cover film with the lower pocket film 10.
[0120] As shown in FIG. 8, the suction unit 150 includes a suction
nozzle 152, which is connected to a vacuum utility line in a
factory or a vacuum pump so as to generate vacuum suction pressure
on the lower pocket film 10, and a screen 154, which is provided at
a position between the suction nozzle 152 and the lower pocket film
10 to prevent mixtures or tablets, filled in the pocket film, from
being drawn upwards by the vacuum suction pressure.
[0121] Here, the suction nozzle 152 may be movable downwards or
upwards such that it approaches the lower pocket film 10 or moves
away therefrom.
[0122] The overall operation of the packaging machine 100 for
preparing a rapidly disintegrating formulation for oral
administration according to the present invention having the
above-mentioned construction will be described below.
[0123] First, a forming film is fed from the film feeding unit 110
at a constant speed. The forming film is pre-heated and pressed by
the film shaping unit 120 such that pockets 10a having container
shapes are formed in the forming film, thus forming the lower
pocket film 10.
[0124] Thereafter, powdery mixtures or tablets are input into the
corresponding pockets 10a of the formed lower pocket film 10 by the
drug material feeding unit 130. The mixtures or tablets filled in
the pocket film are pressed in the corresponding pockets 10a of the
lower pocket film 10 by the pressing unit 140, thus forming tablets
22 having shapes corresponding to that of the pockets 10a.
[0125] Subsequently, undesirable fine powder, which has been on the
lower pocket film 10, is eliminated by vacuum pressure of the
suction unit 150.
[0126] The mixtures or tablets in the lower pocket film 10 are
thereafter heated by the heating unit 160, so that each mixture or
tablet is melted and unified to guarantee a reliable unifying
force, thereby being formed into a rapidly disintegrating
formulation for oral administration.
[0127] Subsequently, the lower pocket film 10, containing the
rapidly disintegrating formulations for oral administration, is
pressed to the upper cover film by the sealing unit 170 and is thus
sealed, thus completing the packaging operation. Thereafter, the
product is cut by the cutting unit 180 into a predetermined
packaging unit.
[0128] Finally, the rapidly disintegrating formulation product,
which has been packaged, is slowly cooled at room temperature in
the packaged state.
[0129] As such, rapidly disintegrating formulations for oral
administration can be conveniently and economically prepared using
mass production through the single process line.
[0130] In the present invention, although the heating process has
been illustrated as being conducted using the heating unit 160 at a
middle step in the packaging process, the heating process may be
conducted after the process of attaching the upper cover film to
the lower pocket film has been conducted, that is, after the
packaging process has been completed. For this, after the process
of packaging the rapidly disintegrating formulation products has
completed, the products may be supplied into a heating chamber such
that the products are separately heated.
[0131] While the invention has been described with respect to the
above specific embodiments, it should be recognized that various
modifications and changes may be made to the invention by those
skilled in the art which also fall within the scope of the
invention as defined by the appended claims.
* * * * *